Use of pregnane-diones or diols as neuropathic analgesic agents

ABSTRACT

The present invention relates to the use of pregnanes in inducing analgesia, preferably without overt sedation, in a mammal in response to neuropathic pain, and compositions and kits therefore.

FIELD OF THE INVENTION

The present invention relates generally to methods of inducing analgesiain response to neuropathic pain which involve administration ofcompounds as shown in formula I, in particular pregnane-diones orpregnane-diols, optionally in association with one or more otheranalgesic compounds such as opioid compounds. The present invention alsorelates to compositions and kits useful in inducing analgesia inresponse to neuropathic pain.

BACKGROUND OF THE INVENTION

The present invention relates generally to the induction of analgesia inresponse to neuropathic pain. In considering the approaches to treatmentof pain it is important to understand the distinction between acute andchronic pain. Acute pain occurs as a result of tissue injury orinflammation and is mediated by chemical, mechanical or thermalstimulation of pain receptors. In contrast, chronic pain in itselfconstitutes a disease which serves no protective biological function.Chronic pain is unrelenting and can persist for years after an initialinjury. Chronic, non-malignant pain predominantly constitutesneuropathic pain which can be defined as pain initiated or caused by aprimary lesion or dysfunction within the nervous system¹. Neuropathicpain is associated with a variety of disease states and presents in theclinic with a range of symptoms².

Neuropathic pain is often reported as having a lancinating or continuousburning character and is often associated with the appearance ofabnormal sensory signs such as allodynia and hyperalgesia Allodynia isdefined as pain resulting from a stimulus which does not normally elicita painful response and hyperalgesia is characterised by an increasedpain response to a stimulus which is normally painful. Some disorderscharacterised by neuropathic pain include monoradiculopathies,trigeminal neuralgia, postherpetic neuralgia, phantom limb pain, complexregional pain syndromes and the various peripheral neuropathies.

Whereas there are numerous effective therapies for acute pains caused byinflammatory processes or acute injury, especially including treatmentwith opioid and non-steroidal anti-inflammatory drugs (NSAIDs),neuropathic pain is an area of largely unmet therapeutic need. Due tothe distinct pathophysiological mechanisms associated with neuropathicpain relative to inflammatory pains, agents useful in treatment ofinflammatory and other pains have reduced effectiveness in neuropathicpain treatment. In particular, the effectiveness of opioids in treatmentof neuropathic pain is diminished relative to inflammatory paintreatment and the dose response curve of opioids in neuropathic pain isshifted to the right of that for inflammatory pain⁵. The conventionalpharmacological mainstays of clinical management of neuropathic pain arethe tricyclic anti-depressants and certain anti-convulsants^(3,4), buteven these achieve clinically significant pain relief (that is greaterthan 50% pain relief) in less than 50% of patients. These agents arealso associated with significant side effect profiles.

There is therefore a pressing need for improved treatment regimes foraddressing the problem of neuropathic pain and it is in this contextthat the present invention has been conceived. Other objects of thepresent invention will become apparent from the following detaileddescription thereof

SUMMARY OF THE INVENTION

According to one embodiment of the present invention there is provided amethod of inducing analgesia in response to neuropathic pain in a mammalwhich comprises administering to the mammal an effective amount of acompound of formula I

wherein

-   -   R₁ is H, OH, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR;    -   R₂ is H, OH, OR or ═O;    -   R₃ is H, OH or C₁-C₄ alkyl;    -   R₄ is H, OH, ═O, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or        —OR;    -   R₅ is H, OH, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR;    -   R₆ is H, OH, ═CH₂ or C₁-C₄ alkyl;    -   R₇ is H, OH, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄        alkanoyl, SH, SR or —OR;    -   and R is C₁-C₄ alkyl, C₂-C₂ alkenyl or C₂-C₄ alkanoyl;        or a pharmaceutically acceptable derivative thereof.

According to another embodiment of the present invention there isprovided a method of inducing analgesia, without overt sedation, inresponse to neuropathic pain in a mammal which comprises administeringto the mammal an effective amount of a compound of formula I or apharmaceutically acceptable derivative thereof.

Another embodiment of the invention provides a composition for inducinganalgesia, without overt sedation, in response to neuropathic pain in amammal comprising a compound of formula I, or a pharmaceuticallyacceptable derivative thereof, together with at least onepharmaceutically acceptable additive.

In a still further embodiment of the present invention there is provideda method of inducing analgesia in response to neuropathic pain in amammal which comprises concurrently or sequentially administering to themammal effective amounts of an analgesic compound, such as an opioid,and a compound of formula I or a pharmaceutically acceptable derivativethereof. Preferably the analgesic compound and compound of formula I, orpharmaceutically acceptable derivative thereof are administered insynergistically effective amounts. Preferably the method does not resultin overt sedation.

The invention also relates to the use of a compound of formula I, or apharmaceutically acceptable derivative thereof, in the manufacture of amedicament for inducing analgesia, preferably without overt sedation, inresponse to neuropathic pain.

In a still further embodiment of the present invention there is provideda kit for inducing analgesia in response to neuropathic pain in a mammalwhich comprises an analgesic compound, such as an opioid, and a compoundof formula I or a pharmaceutically acceptable derivative thereof.

For example, the analgesic compound may be an opioid selected from oneor more of fentanyl, oxycodone, codeine, dihydrocodeine,dihydrocodeinone enol acetate, morphine, desomorphine, apomorphine,pethidine, methadone, dextropropoxyphene, pentazocine, dextromoramide,oxymorphone, hydromorphone, dihydromorphine, noscapine, papaverine,papaveretum, alfentanil, buprenorphine and tramadol and pharmaceuticallyacceptable derivatives thereof.

In a preferred embodiment, R₇ is OH, OR, SH, SR or halogen, morepreferably OH, OR, SH or SR. In another preferred embodiment R₂ is OH orOR, more preferably in the α-conformation.

Preferred compounds of formula I are those wherein

-   -   R₁ is H, OH or methyl;    -   R₂ is OH;    -   R₃ is H or methyl;    -   R₄ is H, OH or ═O;    -   R₅ is H, OH or methyl;    -   R₆ is H or methyl;    -   R₇ is OH, OC₂₋₄alkanoyl (such as OCOCH₃), SH, SCOCH₃, Cl, Br or        F.

In another preferred embodiment R₁ is H, R₂ is OH in alpha conformation,R₃ is methyl (in alpha or beta conformation) and R₇ is OH or OR.

In another preferred embodiment, the compound of formula I is apregnane-dione, ie R₂ or R₄ is ═O.

In a particularly preferred embodiment of the invention, the compoundaccording to formula I is alphadolone acetate.

The compounds according to the invention may be administered, interalia, orally, intravenously, intramuscularly, intraperitoneally,intragastrically, intrathecally. transdermally or intestinally. In aparticularly preferred form, the compounds are administered orally.

Preferably the compound according to formula I is administered up to amaximum dose of about 2 grams/70 kg every 6 hours.

In a particularly preferred embodiment of the invention the mammal is ahuman.

BRIEF DESCRIPTION OF THE FIGURES

The present invention will be further described with reference to thefollowing figures, wherein:

FIG. 1 shows a plot of alphadolone acetate dose (mg/kg) against resttime (seconds) for male Wistar rats intraperitoneally administered60-200 mg/kg of alphadolone acetate. Results for saline contreatedcontrol rats are represented by the broken lines.

FIG. 2 shows a plot of oxycodone dose (mg/kg) against rest time(seconds) for male Wistar rats intraperitoneally administered 0.125-1.0mg/kg of oxycodone. Results for saline contreated control rates areshown by the broken lines.

FIG. 3 shows a bar graph representation of rest counts for oxycodone(0.5 mg/kg) administered intraperitoneally and oxycodone (0.5 mg/kg)combined with alphadolone acetate (10 mg/kg) also administeredintraperitoneally.

FIG. 4 shows a plot of time from drug administration (hours) againstwithdrawal threshold (log grams) for male Wistar rats subjected to theChung neuropathy model of L5 and L6 Tight ligation. Paw withdrawalthreshold was measured before and after intraperitoneal injection ofalphadolone acetate at 20 and 40 mg/kg.

FIG. 5 shows plots of the anti-nociceptive effects in diabeticneuropathic male Wistar rats compared to normal weight matched maleWistar rats following administration of oxycodone (250 μg/kg),alphadolone acetate (a.acetate) (6 mg/kg) or combined oxycodone andalphadolone acetate (a.acetate) at the same doses. Assessment ofanti-nociceptive effects was conducted by monitoring noxious electricalcurrent (ACT) (A), tail flick latency (B) and paw pressure (C).

FIG. 6 shows dose response curves for the anti-nociceptive effect ofintraperitoneally administered fentanyl in control male Wistar rats(FIG. 6A) and intraperitoneally administered fentanyl given alone andalso alphadolone acetate together with fentanyl in diabetic neuropathicmale Wistar rats (FIG. 6B).

FIG. 7 shows dose response curves for the anti-nociceptive effect ofintraperitoneally administered morphine in control male Wistar rats(FIG. 7A) and intraperitoneally administered morphine given alone andalso alphadolone acetate together with morphine in diabetic neuropathicmale Wistar rats (FIG. 7B).

FIG. 8 shows dose response curves for the anti-nociceptive effect ofintraperitoneally administered oxycodone in control male Wistar rats(FIG. 8A) and of intraperitoneally administered oxycodone given aloneand also alphadolone acetate together with morphine in diabeticneuropathic male Wistar rats (FIG. 8B).

FIG. 9 shows dose response curves for the anti-nociceptive effect ofintraperitoneally administered alphadolone acetate in control (FIG. 9A)and diabetic neuropathic (FIG. 9B) male Wistar rats.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

As conveyed above, the present invention relates to methods of inducinganalgesia in response to neuropathic pain in a mammal. In this contextthe term “mammal” is intended to encompass both humans and other mammalssuch as laboratory animals including rats, mice, simians and guineapigs, domestic animals including cats, dogs, rabbits, agriculturalanimals including cattle, sheep, goats, horses and pigs and captive wildanimals such as lions, tigers, elephants and the like.

Throughout this specification, the term “neuropathic pain” is to beunderstood to mean pain initiated or caused by a primary lesion ordysfunction within the nervous system. It is the intention of themethods according to the present invention to induce analgesia inresponse to neuropathic pain being suffered by a mammalian, preferablyhuman, patient. In this context the term “analgesia” is intended todescribe a state of reduced sensibility to pain, which preferably occurswithout overt sedation and preferably without an effect upon the senseof touch. Preferably, the sensibility to pain is reduced by at least30%, preferably at least 50%, more preferably at least 70% andparticularly preferably at least 85%. In the most preferred aspect ofthe invention the sensibility to the neuropathic pain is completely, orsubstantially completely, removed. To assess the level of reduction ofsensibility to pain associated with the analgesia induced by the methodsaccording to the present invention it is possible to conduct tests suchas the short form McGill pain questionnaire and/or visual analogue scalefor pain intensity and/or verbal rating scale for pain intensity and/ormeasurement of tactile allodynia using von Frey hairs or similar device.These tests are standard tests within the art and would be well known tothe skilled person.

By the term “overt sedation” it is intended to convey that the methods(and compositions) of the invention do not result in practicallymeaningful sedation of the patent, ie significant, visible or apparentdrowsiness or unconsciousness of the patient being treated. Thus,administration of preferred compounds described herein do not result insleepiness or drowsiness in the patient to the extent that it interfereswith or inhibits the activities associated with day to day living, egdriving a motor vehicle or operating machinery for human subjects orfeeding and grooming for an animal subject. Where a compound of formulaI, or a pharmaceutically acceptable derivative thereof is administeredconcurrently or sequentially with another analgesic compound, it is tobe understood that “overt sedation” refers to sedation over and aboveany sedation which may be caused by the analgesic compound.

In one embodiment, preferred compounds of Formula I according to thepresent invention are pregnane-dione compounds. As an example, thechemical structure of 3,20-pregane-dione, together with conventionalnumbering of the steroidal ring system is shown in Formula II below.Other pregnane-dione compounds contemplated are 11,20-pregnane-diones.

Compounds encompassed by Formula I and related compounds, such as C20amino pregnanes which may also be useful in the methods describedherein, are for example disclosed in The Merck Index (13th Edition) andAustralian Patent No. 698,746, U.S. Pat. No. 3,558,608, GB Patent No.1,317,184, GB Patent No. 1,317,185 as well as German Patent Nos.2,162,593 and 2,162,554.

The whole of the subject matter of the above documents together withitems 105627c and 9285v of Chemical Abstracts, Vol. 77, 1972; 64113v,64114w, 20793n of Chemical Abstracts 5, Vol. 75, 1971; 115783f and66672h of Chemical Abstracts Vol. 79, 1973; and 1020345 of ChemicalAbstracts Vol. 78, 1973 is to be considered included and importedhereinto.

The documents referred to above provide details of synthetic approacheswhich may be adopted in production of compounds according to Formula I.Other compounds may be available commercially from sources such asSteraloids (Newport, R.I.) or be naturally occurring. Still othercompounds may be obtained by chemical manipulation, using standardmethods known in the art, of compounds such as those described in thereferences above.

A particularly preferred compound according to Formula I is21-acetoxy-3α-hydroxy-5α-pregnane-11,20-dione which is commonly referredto as alphadolone acetate and is depicted in Formula III.

Another compound of formula I contemplated by the invention is thedeacylated form of alphadolone acetate:

Yet another compound of formula I contemplated by the invention is:

Other preferred compounds according to the invention may include3α-hydroxy-5α-pregane-11,20-dione;3α-hydroxy-21-propionyloxy-5α-pregane-11,20-dione;21-iso-butyryloxy-3α-hydroxy-5α-pregnane-11,20-dione;21-hemisuccinyloxy-3α-hydroxy-5α-pregane-11,20-dione; 3α-hydroxy-5β-pregnan-20-one; and 3α-hydroxy-5β-pregnan-20-one;(3α-5α)-3,17,21-trihydroxy-pregnan-1,20-dione;(3α-5β)-3,17,21-trihydroxy-0pregnan-11,20-dione;3β,17βα,21-trihydroxy-5α-pregnan-11,20-dione; 3β,11β,21-trihydroxy-5α-pregnan-11,20-dione;3β,17α,21-trihydroxy-5α-pregnan-20-one; 5α-pregnan-3,20-dione and5β-pregnan-3,20-dione.

Particularly preferred compounds of the invention have an oxy or thiogroup at the 21-position, eg where R₇ is OH, SH, OR (eg OC₂₋₄alkanoyl)or SR, more preferably OH or OR. Other preferred embodiments of theinvention are compounds of formula I, or pharmaceutically acceptablederivatives thereof, which are capable of forming a glucuronidemetabolite once administered to the patient. Still other preferredcompounds are pregnane-dione compounds, eg where R₂ or R₄ is ═O. Inanother embodiment, R₅ and R₆ are hydrogen. In another embodiment, R₇ isOC₂-C₄alkanoyl. In still another preferred embodiment of the invention,R₇ and R₂ are both independently selected from the group of OH and OR,eg R₂ is OH and R₇ is OH or OR. Other preferred compounds are thosewhere R₃ is β-methyl. Particularly preferred compounds of formula I maypossess, where appropriate, two or more of the above preferred features.

With reference to Formula I, it will of course be well understood by aperson skilled in the art that substitutents not specifically defined,but the presence of which is necessary due to extra valency, will betaken up by hydrogen atoms. It will also be understood in the situationwhere for example, R₂ represents an oxo radical at the 3 carbonposition, there will be no hydrogen bound at this position. This alsoapplies when R₄ is oxo and R₆ is methylene.

The term “alkyl” used herein denotes straight chain, branched ormonocyclic alkyl, preferably including from 1-4 carbon atoms. Examplesof straight chain, branched and cyclic alkyls include methyl, ethyl,propyl, isopropyl, butyl, cyclopropyl and cyclobutyl.

The term “alkenyl” used herein denotes groups formed from straightchain, branched or cyclic alkenes, including mono- or poly-unsaturatedalkyl or cycloalkyl groups. Specific examples include vinyl, allyl,1-methylvinyl, butenyl and isobutenyl.

The term “alkanoyl” is intended to denote straight or branched chainalkanoyl (COalkyl) groups such as acetyl (COCH₃), propionyl (COCH₂CH₃),butyryl (COCH₂CH₂CH₃) and isobutyryl (COCH(CH₃)₂).

In another aspect of the present invention the method of inducinganalgesia in response to neuropathic pain may involve concurrent orsequential administration to the mammal in need of such treatment ofadditively, or more preferably, synergistically effective amounts of acompound of formula I, or a pharmaceutically acceptable derivativethereof, and another analgesic compound such as an opioid. Thus, asynergistically effective amount of a compound of formula (I), orpharmaceutically acceptable derivative thereof, when administeredconcurrently or sequentially with an opioid may restore opioidresponsiveness to neuropathic pain. The compound of formula I, orpharmaceutically acceptable derivative thereof, and the opioid may beadministered either as a combined form, ie a single compositioncontaining the active agents, or as discrete dosages. The active agentsare temporally administered such that the desired additive orsynergistic analgesic effect is achieved.

As used herein, opioid compounds (opioids) include any compound which isa partial or full agonist of an opioid receptor.

Opioid compounds are well known and include naturally occurringcompounds derived from opium such as codeine, morphine and papavarine aswell as derivatives of such compounds which generally have structuralsimilarity and other compounds which are active as analgesic agents.Specific examples of opioid compounds contemplated by the presentinvention may include: fentanyl, oxycodone, codeine, dihydrocodeine,dihydrocodeinone enol acetate, morphine, desomorphine, apomorphine,pethidine, methadone, dextropropoxyphene, pentazocine, dextromoramide,oxymorphone, hydromorphone, dihydromorphine, noscapine, papaverine,papaveretum, alfentanil, buprenorphine and tramadol and pharmaceuticallyacceptable derivatives and/or tautomers thereof.

The phrase “pharmaceutically acceptable derivative” is intended toconvey any pharmaceutically acceptable salt, pro-drug, hydrate, solvate,metabolite or any other compound which, upon administration to thesubject, is capable of providing (directly or indirectly) the compoundconcerned or a physiologically (eg analgesically) equivalent activecompound, or an active metabolite or residue thereof. An example of asuitable derivative is an ester formed from reaction of an OH or SH (egC21 OH or SH) group with a suitable carboxylic acid, for exampleC₁₋₃alkyl-CO₂H, and HO₂C—(CH₂)_(n)—CO₂H (where n is 1-10, preferably14), and CO₂H—CH₂phenyl.

Thus, the compounds of formula I may be in crystalline form, either asthe free compounds or as solvates (eg hydrates). Methods of solvationare generally known within the art.

The salts of the active compounds of the invention are preferablypharmaceutically acceptable, but it will be appreciated thatnon-pharmaceutically acceptable salts also fall within the scope of thepresent invention, since these are useful as intermediates in thepreparation of pharmaceutically acceptable salts. Examples ofpharmaceutically acceptable salts include salts of pharmaceuticallyacceptable cations such as sodium, potassium, lithium, calcium,magnesium, ammonium and alkylammonium; acid addition salts ofpharmaceutically acceptable inorganic acids such as hydrochloric,orthophosphoric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamicand hydrobromic acids; or salts of pharmaceutically acceptable organicacids such as acetic, propionic, butyric, tartaric, maleic,hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic,succinic, oxalic, phenylacetic, methanesulphonic,trihalomethanesulfphonic, toluenesulphonic, benzenesulphonic,salicyclic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic,oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

The term “pro-drug” is used herein in its broadest sense to includethose compounds which can be converted in vivo to the compound ofinterest (eg by enzymatic or hydrolytic cleavage). Examples thereofinclude esters, such as acetates of hydroxy or thio groups, as well asphosphates and sulphonates. Processes for acylating hydroxy or thiogroups are known in the art, eg by reacting an alcohol (hydroxy group),or thio group, with a carboxylic acid. Other examples of suitablepro-drugs are described in Design of Prodrugs, H. Bundgaard, Elsevier,1985.

The term “metabolite” includes any compound into which a compound offormula I can be converted in vivo once administered to the subject.Examples of such a metabolite are a glucuronide, a sulphate andhydroxylates.

It will be understood that the compounds as described herein may existin a tautomeric form to that depicted, ie as a tautomer thereof. Theterm “tautomer” is used herein in its broadest sense to includecompounds which are capable of existing in a state of equilibriumbetween two isomeric forms. Such compounds may differ in the bondconnecting two atoms or groups and the position of these atoms or groupsin the compound. A specific example is keto-enol tautomerism.

The compounds of the invention may be electrically neutral or bepolycations with associated anions for electrical neutrality. Suitableassociated anions include sulfate, tartrate, citrate, chloride, nitrate,nitrite, phosphate, perchlorate, halosulfonate ortrihalomethylsulfonate.

Neuropathic pain which may be treated by the methods of the inventioninclude monoradiculopathies, trigeminal neuralgia, postherpeticneuralgia, phantom limb pain, complex regional pain syndromes,neuropathic pain associated with AIDS and infection with the humanimmunodeficiency virus and the various peripheral neuropathies,including, but not limited to drug-induced and diabetic neuropathies.

The compounds of Formula I, and pharmaceutically acceptable thereof, andthe analgesic compounds (eg opiates) which may be optionallyadministered in conjunction with them (referred to as the “activeingredients, agents or compounds”) may be administered for therapy byany suitable route. It will be understood that compounds of formula I ortheir derivatives are preferably administered via a route which does notresult in overt sedation of the subject. Suitable routes ofadministration may include oral, rectal, nasal, inhalation of aerosolsor particulates, topical (including buccal and sublingual), transdermal,vaginal, intravesical and parenteral (including subcutaneous,intramuscular, intravenous, intrastemal, intrathecal, epidural andintradermal). Preferably, administration of a compound of formula I or apharmaceutically acceptable derivative thereof will be by a route whichwhen administered first presents the compound to the stomach of thesubject. In a particularly preferred embodiment of the invention, thecompound of formula I is administered via an oral route, however it willbe appreciated that the preferred route will vary with the condition andage of the subject, the nature of the neuropathic pain being treated,its location within the subject and the judgement of the physician orveterinarian.

As used herein, an “effective amount” refers to an amount of activecompound which provides the desired analgesic activity when administeredaccording to a suitable dosing regime. Preferably the amount of acompound of formula I, or pharmaceutically acceptable derivative thereofis an amount which provides the desired analgesic activity withoutcausing overt sedation. Dosing may occur at intervals of minutes, hours,days, weeks or months. Suitable dosage amounts and regimes can bedetermined by the attending physician or veterinarian. For example,compounds of formula I, or pharmaceutically acceptable derivativesthereof, may be administered to a subject at a rate of 50 to 2000 mgevery six hours, such as 50-500 mg. Dosing of the analgesic agent, suchas an opioid, can be determined by the attending physician in accordancewith dosing rates in practice. For example, fentanyl can be administeredin an amount of about 100 μg whereas morphine may be administered in anamount of 1-5 grams.

The compositions of the present invention comprise at least one compoundof Formula I or pharmaceutically acceptable derivative thereof,optionally with an analgesic compound such as an opioid, together withone or more pharmaceutically acceptable additives such as carriers,diluents adjuvants and/or excipients and optionally other medicaments.These include all conventional solvents, dispersion agents, fillers,solid carriers, coating agents, antifungal or antibacterial agents,dermal penetration agents, surfactants, isotonic and absorption agentsand slow or controlled release matrices. Compositions for use in thepresent invention may also include other supplementary physiologicallyactive agents, eg other analgesic agents. The compounds may be presentedin the form of a kit of components which is adapted for allowingconcurrent or sequential administration of the active components. Eachcarrier, diluent, adjuvant and/or excipient must be pharmaceutically“acceptable” in the sense of being compatible with the other ingredientsof the composition and not injurious to the subject. The compositionsmay conveniently be presented in unit dosage form and may be prepared bymethods well known in the art of pharmacy. Such methods include the stepof bringing into association the active ingredient with the carrierwhich constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers, diluents,adjuvants and/or excipients or finely divided solid carriers or both,and then if necessary shaping the product.

Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous phase ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil emulsion. The active ingredient may also be presented as abolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder (e.g. inert diluent, preservative disintegrant (eg. sodium starchglycollate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) surface-active or dispersing agent. Moulded tablets may bemade my moulding in a suitable machine a mixture of the powderedcompound moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and may be formulated so as to provideslow or controlled release of the active ingredient therein using, forexample, hydroxypropylmethyl cellulose in varying proportions to providethe desired release profile. Tablets may optionally be provided with anenteric coating, to provide release in parts of the gut other than thestomach.

Compositions suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render thecomposition isotonic with the blood of the intended subject; and aqueousand non-aqueous sterile suspensions which may include suspended agentsand thickening agents. The compositions may be presented in a unit-doseor multi-dose sealed containers, for example, ampoules and vials, andmay be stored in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example water forinjections, immediately prior to use. Extemporaneous injection solutionsand suspensions may be prepared from sterile powders, granules andtablets of the kind previously described.

Compositions suitable for topical administration to the skin, ietransdermal administration, may comprise the active compounds dissolvedor suspended in any suitable carrier or base and may be in the form oflotions, gels, creams, pastes, ointments and the like. Suitable carriersmay include mineral oil, propylene glycol, waxes polyoxyethylene, andlong chain alcohols. Transdermal devices, such as patches may also beused and may comprise a microporous membrane made from suitable materialsuch as cellulose nitrate/acetate, propylene and polycarbonates. Thepatches may also contain suitable skin adhesive and backing materials.

The compounds of formula I may also be presented as implants which maycomprise a drug bearing polymeric device wherein the polymer isbiocompatible and non-toxic. Suitable polymers may include hydrogels,silicones, polyethylenes and biodegradable polymers.

The compounds of the invention may be administered in a sustained (iecontrolled) or slow release form. A sustained release preparation is onein which the active ingredient is slowly released within the body of thesubject once administered and maintains the desired drug concentrationover a minimum period of time. The preparation of sustained releaseformulations is known to the skilled person. Dosage forms may includeoral forms, implants and transdermal forms. For slow releaseadministration, the active ingredients may be suspended as slow releaseparticles or within liposomes

It should be understood that in addition to the ingredients particularlymentioned above, the composition of this invention may include otheragents conventional in the art having regard to the type of compositionin question, for example, those suitable for oral administration mayinclude such further agents as binders, sweetners, thickeners,flavouring agents, disintegrating agents, coating agents, preservatives,lubricants and/or time delay agents.

Other details of pharmaceutically acceptable carriers, diluents andexcipients and methods of preparing pharmaceutical compositions andformulations are provided in Remmingtons Pharmaceutical Sciences 18^(th)Edition, 1990, Mack Publishing Co., Easton, Pa., USA, the disclosure ofwhich is included herein in its entirety by way of reference.

The compounds for use in the invention may also be presented for use inveterinary compositions. These may be prepared by any suitable meansknown in the art. Examples of such compositions include those adaptedfor:

-   -   (a) oral administration, eg drenches including aqueous and        non-aqueous solutions or suspensions, tablets, boluses, powders,        granules, pellets for admixture with feedstuffs, pastes for        application to the tongue;    -   (b) parenteral administration, eg subcutaneous, intramuscular or        intravenous injection as a sterile solution or suspension;    -   (c) topical application, eg creams, ointments, gels, lotions,        etc.

Particularly preferred compounds according to Formula I includealphadolone acetate and alphadolone glucuronide or other pro-drug whichwill provide a 21-OH group in vivo. If other salt forms of active agentsaccording to Formula I are adopted it is preferred to adopt eithersulfate or methane sulfonate salts, more preferably at the C21 position.

In a particularly preferred embodiment of the invention the compoundaccording to Formula I is administered orally, preferably in the form ofa tablet, capsule, lozenge or liquid. The administered composition willpreferably include a surfactant and/or solubility improver. A suitablesolubility improver is water-soluble polyethoxylated caster oil and anexample of a suitable surfactant is Cremophor EL. Dose ranges suitablefor alphadolone or the pregnane-diones are for example 50 to 500 mgorally, every six hours. Suitable dose ranges for morphine are 2.5 to 20mg every 3 to 6 hours and for oxycodone and other opioids 2 to 50 mgevery 3 to 12 hours.

EXAMPLES

The present invention will now be further described with reference tothe following examples which are intended for the purpose ofillustration only and are not intended to limit the generalityhereinbefore described.

Example 1

Animal Models of Neuropathic Pain—Experimental Approach

There are no human experimental neuropathic pain models. There areseveral animal models that differ in the method of induction of pain andin the relative balance of signs and symptoms. Thus researchers, inattempting to identify a useful pharmacotherapy, will use a battery ofthese models.

The majority of neuropathic pain models in current use share as a commonfeature alterations in hind-limb cutaneous sensory thresholds followingpartial injury of a peripheral (usually sciatic) nerve. In particular,demonstration of hyperalgesia to noxious thermal stimuli and allodyniato cold and mechanical stimuli are used as outcome measures. Two of themost commonly used models are the chronic constriction injury (CCI) ofsciatic nerve,⁷ and the spinal nerve ligation model (SNL)⁶. The CCImodel consists of the loose ligation of the sciatic nerve at mid-thighlevel with chromic gut sutures⁷. An inflammatory reaction develops inresponse to the catgut and consequentially a loss of most A-fibres andsome C-fibres, but few cell bodies⁸. This is associated with spontaneouspain-related behaviour, allodynia and hyperalgesia. The SNL model (Chungmodel) consists of injury to the L5 and L6 spinal nerves, whichcontribute to the sciatic nerve⁶. Once again, this is associated withthe development of spontaneous pain-like behaviour as well as longlasting allodynia and hyperalgesia.

The majority of animal models of neuropathy have been based on adiscrete peripheral nerve injury. However, some have been developed tomore closely mimic individual disease states. An example of this is thestreptozotocin model of peripheral diabetic neuropathy⁹. In this model,injections of streptozotocin induce diabetes and then hyperalgesia andallodynia.

In the present investigations the sedative effects of alphadoloneacetate and an opioid, oxycodone, were investigated when the drugs weregiven alone and also together. Non sedative doses so identified weretested for analgesic efficacy in two rat neuropathic pain models, theChung model of tight L5/6 nerve root ligation, andstreptozotocin-induced diabetic neuropathy. Alphadolone acetate was usedas an example of analgesic neurosteroids that have the unique propertyof analgesic properties by an action on spinal cord GABA_(A) receptorsand oxycodone was chosen to typify the behaviour and results expected ofa range of opioid drugs used clinically.

(i) Examination of Sedation Effects

Male Wistar rats (n=10 per dosage group) were given a range of doses ofalphadolone acetate (60 to 200 mg/kg intraperitoneally in 10% CremophorEL) or oxycodone (0.125 to 1.0 mg/kg intraperitoneally in saline) aloneand also oxycodone (0.5 mg/kg) at the same time as a dose of alphadoloneacetate (10 mg/kg, both intraperitoneally). These rats were naive to thedrugs and also to the open field activity monitor. After the injectionof drug or drug combination the activity of each rat was monitored bythe breaking of a grid of intersecting infrared beams in a dark box. Theresting time calculated from the number of beam breaks were counted for30 minutes. The ten replicate observations for each drug dose werecombined and means +/−SEM plotted on dose response curves alongsidesaline controls.

The results for resting times in the experiments using the open fieldactivity monitor are shown below for alphadolone acetate and oxycodonegiven alone compared with saline controls (FIGS. 1 and 2) and foroxycodone 0.5 mg/kg given alone and with alphadolone acetate 10 mg/kg(FIG. 3).

Doses of alphadolone acetate less than 100 mg/kg and oxycodone less than1.0 mg/kg did not increase resting times compared with saline controls.Lower doses of each drug (alphadolone acetate 60 mg/kg; oxycodone 0.25and 0.125 mg/kg) actually decreased resting times compared with salinecontrols. Furthermore the addition of 10 mg/kg alphadolone acetate to0.5 mg/kg oxycodone did not cause any increase in sedation assessed byresting time in the open field activity monitor. Thus anyanti-nociceptive activity observed in neuropathic pain models that thesedoses or lower of each drug given alone or in combination might exhibitcould not be explained by the occurrence of sedation.

(ii) Chung Neuropathic Pain Model

Rats were prepared with tight nerve root ligations according to themethod described by Kim and Chung⁶. The paw withdrawal thresholds weremeasured before and after intraperitoneal injections of alphadolone (20and 40 mg/kg; n=10 per group). This was achieved using a Randall Sellitoapparatus in which an increasing weight was applied to the neuropathicpaw. The paw withdrawal threshold was the weight at which the ratwithdrew its paw from the apparatus.

This is a model of neuropathic pain in which allodynia is induced in onehind paw of the rat by tight ligatures placed on the ipsilateral lumbardorsal rootlets. The results in this model for groups of 10 rats thatreceived alphadolone acetate intraperitoneally are shown in FIG. 4. Itcan be seen that the nerve ligation reduces the threshold of withdrawalfrom a mechanical stimulus from normal nociceptive stimulus levelspre-op to levels that are normally non-nociceptive at time 0 whenalphadolone was administered.

(iii) Diabetic Neuropathic Pain Model

Seventy rats were injected intraperitoneally with streptozotocin (STZ)(150 mg/kg total dose) (Sapphire Bioscience) dissolved in sodiumchloride (0.9%). The 150 mg dose was given in two 75 mg/kg injections onconsecutive days. An additional group of animals was injected withsaline to act as a vehicle control (n=10). Diabetes was confirmed oneweek after injection of STZ by measurement of tail vein blood glucoselevels with Ames Glucofilm test strips and a reflectance colorimeter(Ames Glucometer 3, Bayer Diagnostics). Only animals with final bloodglucose levels ≧15 mM were deemed to be diabetic. The rats were retestedfor hyperglycaemia immediately after each session of nociceptivetesting. Hyperalgesia was assessed using the paw pressure test,previously described by Randall and Selitto (Randall L. O, Selitto, J.J. 1957 A Method for Measurement of Analgesic Activity in InflamedTissue Archiv. Int. Pharmacodynamie: 111; 409). Replicate results ineach group were combined to calculate means +/−SEM that were plotted ashistograms. Tests took place 5 weeks after the first injection of STZ.Animals that had paw pressure nociceptive thresholds below 30 g (60% ofthe value in normal weight matched rats) were deemed to have developedhyperalgesia/neuropathic pain and thus used in further experiments. Thiswas 91% of all STZ treated rats.

The anti-nociceptive effects of alphadolone acetate (6 mg/kg ip) andoxycodone (250 μg/kg) each given alone and in combination to groups ofnormal weight matched and diabetic neuropathic rats (n=10 per group)were assessed with noxious electrical current (ECT), tail flick latency(TFL) and paw pressure.

The anti-nociceptive effects assessed with noxious electrical current(ECT), tail flick latency (TFL) and paw pressure of alphadolone acetate(6 mg/kg ip) and oxycodone (250 μg/kg) each given alone and incombination to groups of normal weight matched and diabetic neuropathicrats are shown in FIG. 5 (A, B, and C respectively).

It can be seen that diabetic neuropathic pain is minimally responsive tothe anti-nociceptive action of the opioid or alphadolone acetate wheneither drug is used alone. However, the combination of both drugs led toanti-nociception equal in magnitude to that obtained in normal rats withthe opioid. The doses of the neurosteroid and opioid used alone or thecombination were well below those that cause sedation as assessed by theopen field activity monitor. Importantly, the anti-nociceptive effectshown when opioid and alphadolone acetate were administered together wasgreater than that expected from addition of their individual effects.

Example 2

Model for Neuropathic Pain

Courteix and co-workers have developed a diabetes-induced model forneuropathic pain.

They found that induction of experimental insulin-dependent diabetesmellitus in rats caused allodynia and hyperalgesia¹⁰. They went on toshow that intravenous morphine induced a dose-dependent anti-nociceptiveeffect at doses twice as high as those in normal rats using themechanical nociceptive paw pressure test¹⁰. Thus the diabetic modelreproduced the experience of diabetic neuropathic pain in humans; it isopioid resistant. The experiments reported here use this model to assessthe relative efficacy of alphadolone acetate and three opioids,fentanyl, morphine and oxycodone given alone and in combinations incausing anti-nociception assessed with paw pressure measured using theRandall Sellito method.

Methods:

Male Wistar rats (wt 65-80 g) were used for these experiments. Animalswere housed 5 per cage under standard laboratory conditions. Food andwater were provided ad libitum.

(i) Induction of Diabetes/Hyperalgesia

Rats were injected intraperitoneally (IP) with streptozotocin (STZ) (150mg/kg total dose) (Sapphire Bioscience) dissolved in sodium chloride(0.9%). The 150 mg dose was given in two 75 mg/kg injections onconsecutive days. Diabetes was confirmed one week after injection of STZby measurement of tail vein blood glucose levels with Ames Glucofilmtest strips and a reflectance colorimeter (Ames Glucometer 3, BayerDiagnostics). Only animals with final blood glucose levels ≧15 mM weredeemed to be diabetic. The rats were retested for hyperglycaemia onceper week to confirm continued high blood glucose readings. Hyperalgesiawas assessed using the paw pressure test, previously described byRandall and Selitto¹¹.

Tests took place 5 weeks after the first injection of STZ. Animals thathad paw pressure nociceptive thresholds below 30 g (60% of the value innormal weight matched rats) were deemed to have developedhyperalgesia/neuropathic pain and thus used in further experiments. Thiswas 25% of all STZ treated rats in this series of experiments.

(ii) Nociceptive Tests

After the successful documentation of the development of hyperalgesia indiabetic animals by the paw pressure test, more extensive nociceptivetesting paradigms were carried out in diabetic neuropathic animals andweight-matched controls; the control rats were 1-2 weeks younger. Pawpressure (PP) was measured by the method described by Randall andSelitto¹¹ using a Ugo-Basile Algesimeter (Apelex; probe 1 mm; weight:log; increasing pressure to the left hind paw was applied untilvocalisation was elicited. The following protocol was used in eachexperiment in groups of rats (n=4-8) with diabetic neuropathy and normalweight matched controls:

-   -   paw withdrawal thresholds measured every 5 minutes for 15        minutes to give readings a, b, and c    -   intraperitoneal injection of drug or drug combination    -   paw withdrawal thresholds measured every 5 minutes for a further        35 minutes to give readings d, e, f, g, h, i, and j

The starting thresholds a, b and c varied between individual rats. Thus,in order to obtain meaningful results the responses to theintraperitoneal drugs were standardised according to the equation belowin neuropathic rats.${\%\quad{maximum}\quad{effect}} = {\frac{\left( {{{mean}\quad{of}\quad h},i,j} \right) - \left( {{{mean}\quad{of}\quad a},b,c} \right)}{(X) - \left( {{{mean}\quad{of}\quad a},b,c} \right)} \times 100}$and standardised according to the equation below in normal weightmatched controls${{threshold}\quad{increase}\quad{as}\quad{ratio}\quad{of}\quad{starting}\quad{level}} = {1 + \frac{\left( {{{mean}\quad{of}\quad h},i,j} \right) - \left( {{{mean}\quad{of}\quad a},b,c} \right)}{(X)}}$in which X represents the mean of all predrug paw pressure thresholds inweight matched normal rats. In normal weight matched rats, a response socalculated of 2.0 would indicate that the drug treatment doubled thenociceptive threshold for paw pressure. In diabetic neuropathic rats a100% response so calculated means that the drug or drug combinationelevated the paw withdrawal threshold to the threshold found in normalrats; the allodynia and hyperalgesia was reversed totally. Results forreplicate experiments with a particular drug or drug combination at eachdose were combined and expressed as means and SEM.

The experiments were performed in a blinded fashion i.e. the personperforming the measurements of paw pressure thresholds was unaware ofthe doses of drugs given. Dose reponse curves were constructed for eachof the opioids given alone in normal weight matched control rats andalso for each of the opioids given alone and in combination with 1.0mg/kg intraperitoneal alphadolone acetate in rats with diabeticneuropathy. In addition dose response curves were constructed foralphadolone acetate given alone in normal weight matched control rats aswell as rats with diabetic neuropathy.

(iii) Results

FIGS. 6A, 7A and 8A show dose response curves for each of 3 opioids innormal rats and in diabetic neuropathic rats. In all cases doses ofopioids that caused significant antinociception in normal weight matchedrats caused little or no reversal of the allodynia and hyperalgesia inrats with diabetic neuropathy.

Alphadolone acetate, on the other hand, as can be seen in FIG. 9, causeddose related anti-nociceptive effects in rats with diabetic neuropathywith the same potency as for anti-nociceptive responses in normal weightmatched rats. The two dose response curves overlay each other. Themaximum dose of alphadolone acetate used in these studies (10 mg/kg)reversed 80% of the allodynia and hyperalgesia to paw pressure indiabetic neuropathic rats.

When 1.0 mg/kg alphadolone acetate, which is ineffective in causinganti-nociception when given alone, was coadministered with each of theopioids in diabetic neuropathic rats, significant anti-nociceptionoccurred (FIGS. 6B, 7B, and 8B) Doses of opioids that were ineffectivewhen given alone completely reversed the allodynia and hyperalgesia topaw pressure in diabetic neuropathic rats.

It should be understood that the present invention has been described byway of example only and that modifications and/or alterations theretowhich would be apparent to a skilled person based upon the disclosureherein are also considered to fall within the scope and spirit of theinvention.

REFERENCES

-   1 Merskey H, Bogduk N. Classification of Chronic Pain, 2nd edn.    Seattle: IASP Press, 1994; 394-   2 Woolf C J and Mannion R J. Pain: neuropathic pain: aetiology,    symptoms, mechanisms and management. Lancet 1999; 353: 1959-64-   3 McQuay H J, Tramer M, Nye B A, Carroll D, Wiffen P J, Moore R A. A    systematic review of antidepressants in neuropathic pain. Pain 1996;    68: 217-27-   4 Sindrup S H, Jensen T S. Efficacy of pharmacological treatments of    neuropathic pain: an update and effect related to mechanism of drug    action. Pain 1999; 83: 389-400-   5 Rowbotham M C. Kalso E, McQuay H J, Wiesenfeld-Hallin Z, eds. The    debate over opioids and neuropathic pain. Opioid Sensitivity of    Chronic Non-cancer Pain. Seattle: IASP Press, 1999; 18: 307-17-   6 Kim S H, Chung J M. An experimental model for peripheral    neuropathy produced by segmental spinal nerve ligation in the rat.    Pain 1992; 50: 355-63-   7 Bennett G J, Xie Y K. A peripheral mononeuropathy in rat that    produces disorders of pain sensation like those seen in man. Pain    1988; 33: 87-107-   8 Tandrup T, Woolf C J, Coggeshall R E. Delayed loss of small dorsal    root ganglion cells after transection of the rat sciatic nerve. J    Comp Neurol 2000; 422: 172-80-   9 Malcangio M, Tomlinson D R. A pharmacologic analysis of mechanical    hyperalgesia in streptozotocin/diabetic rats. Pain 1998; 76: 151-7-   10 Courteix, C., Eschalier, A., and Lavarenne, J.,    Streptozocin-induced diabetic rates: behavioural evidence for a    model of chronic pain, Pain, 1993, 63, 81-88.-   11 Randell, L. O., and Selitto, J. J., A method for measurement of    analgesic activity of inflamed tissue, Archiv. Inst. Pharmacdynamie,    1957, 111, 409.

1. A method of inducing analgesia in response to neuropathic pain in amammal which comprises administering to the mammal an effective amountof a compound of formula I

wherein R₁ is H, OH, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR;R₂ is H, OH, OR or ═O; R₃ is H, OH or C₁-C₄ alkyl; R₄ is H, OH, ═O,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR; R₅ is H, OH, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR; R₆ is H, OH, ═CH₂ or C₁-C₄alkyl; R₇ is H, OH, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl,SH, SR or —OR; and R is C₁-C₄ alkyl, C₂-C₂ alkenyl or C₂-C₄ alkanoyl; ora pharmaceutically acceptable derivative thereof.
 2. A method accordingto claim 1 wherein R₇ is OH, SH, OR or SR.
 3. The method according toclaim 1 wherein R₁ is H, OH or methyl; R₂ is OH; R₃ is H or methyl; R₄is H, OH or ═O; R₅ is H, OH or methyl; R₆ is H or methyl; R₇ is OH,OCOCH₃, SH, SCOCH₃, Cl, Br or F.
 4. The method according to claim 2wherein R₁ is H, R₂ is OH in alpha conformation, R₃ is methyl and R₇ isOH or OR.
 5. The method according to claim 3 wherein R₃ is methyl inalpha conformation.
 6. The method according to claim 1 wherein R₂ or R₄is ═O.
 7. The method according to claim 1 wherein R₂ and R₇ areindependently selected from OH and OR.
 8. The method according to claim1 wherein the compound according to formula I is alphadolone acetate. 9.The method according to claim 1 wherein the compound according toformula I is administered orally.
 10. The method according to claim 1wherein the compound according to formula I is administeredintravenously, intramuscularly, intraperitoneally, intragastrically,intestinally, transdermally or intrathecally.
 11. The method accordingto claim 1 wherein the neuropathic pain is selected from the groupconsisting of monoradiculopathies, trigeminal neuralgia, postherpeticneuralgia, phantom limb pain, complex regional pain syndromes,neuropathic pain associated with AIDS or infection with the humanimmunodeficiency virus and drug-induced and diabetic neuropathy.
 12. Themethod according to claim 1 wherein the compound according to formula Iis administered up to a maximum dose of about 2 grams/70 kg every 6hours.
 13. The method according to claim 1 wherein the mammal is ahuman.
 14. A method of inducing analgesia, without overt sedation, inresponse to neuropathic pain in a mammal which comprises administeringto the mammal an effective amount of a compound of formula I

wherein R₁ is H, OH, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR;R₂ is H, OH, OR or ═O; R₃ is H, OH or C₁-C₄ alkyl; R₄ is H, OH, ═O,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR; R₅ is H, OH, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR; R₆ is H, OH, ═CH₂ or C₁-C₄alkyl; R₇ is H, OH, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl,SH, SR or —OR; and R is C₁-C₄ alkyl, C₂-C₂ alkenyl or C₂-C₄ alkanoyl; ora pharmaceutically acceptable derivative thereof.
 15. A method accordingto claim 14 wherein R₇ is OH, SH, OR or SR.
 16. The method according toclaim 14 wherein R₁ is H, OH or methyl; R₂ is OH; R₃ is H or methyl; R₄is H, OH or ═O; R₅ is H, OH or methyl; R₆ is H or methyl; R₇ is OH,OCOCH₃, SH, SCOCH₃, Cl, Br or F.
 17. The method according to claim 16wherein R₁ is H, R₂ is OH in alpha conformation, R₃ is methyl and R₇ isOH or OR.
 18. The method according to claim 16 wherein R₃ is methyl inalpha or beta conformation.
 19. The method according to claim 14 whereinR₂ or R₄ is ═O.
 20. The method according to claim 14 wherein R₂ and R₇are independently selected from OH and OR.
 21. The method according toclaim 14 wherein the compound according to formula I is alphadoloneacetate.
 22. The method according to claim 14 wherein the compoundaccording to formula I is administered orally.
 23. The method accordingto claim 14 wherein the compound according to formula I is administeredintravenously, intramuscularly, intraperitoneally, intragastrically,intestinally, transdermally or intrathecally.
 24. The method accordingto claim 14 wherein the neuropathic pain is selected from the groupconsisting of monoradiculopathies, trigeminal neuralgia, postherpeticneuralgia, phantom limb pain, complex regional pain syndromes,neuropathic pain associated with AIDS or infection with the humanimmunodeficiency virus and drug-induced and diabetic neuropathy.
 25. Themethod according to claim 14 wherein the compound according to formula Iis administered up to a maximum dose of 2 grams/70 kg every 6 hours. 27.The method according to claim 14 wherein the mammal is a human.
 27. Amethod of inducing analgesia in response to neuropathic pain in a mammalwhich comprises concurrently or sequentially administering to the mammaleffective amounts of an analgesic compound and a compound of formula Ior a pharmaceutically acceptable derivative thereof.

wherein R1 is H, OH, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR;R₂ is H, OH, OR or ═O; R₃ is H, OH or C₁-C₄ alkyl; R₄ is H, OH, ═O,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR; R₅ is H, OH, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR; R₆ is H, OH, ═CH₂ or C₁-C₄alkyl; R₇ is H, OH, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl,SH, SR or —OR; and R is C₁-C₄ alkyl, C₂-C₂ alkenyl or C₂-C₄ alkanoyl; orpharmaceutically acceptable derivatives thereof.
 28. A method accordingto claim 27 wherein R₇ is OH, SH, OR or SR.
 29. The method according toclaim 27 wherein R₁ is H, OH or methyl; R₂ is OH; R₃ is H or methyl; R₄is H, OH or; R₅ is H, OH or methyl; R₆ is H or methyl; R₇ is OH, OCOCH₃,SH, SCOCH₃, Cl, Br or F.
 30. The method according to claim 29 wherein R₁is H, R₂ is OH in alpha conformation, R₃ is methyl and R₇ is OH or OR.31. The method according to claim 29 wherein R₃ is methyl in alpha orbeta conformation.
 32. The method according to claim 27 wherein R₂ or R₄is ═O.
 33. The method according to claim 27 wherein R₂ and R₇ areindependently selected from OH and OR.
 34. The method according to claim27 wherein the compound according to formula I is alphadolone acetate.35. The method according to claim 27 wherein the analgesic compound isan opioid.
 36. The method according to claim 35 wherein the opioid isselected from one or more of fentanyl, oxycodone, codeine,dihydrocodeine, dihydrocodeinone enol acetate, morphine, desomorphine,apomorphine, pethidine, methadone, dextropropoxyphene, pentazocine,dextromoramide, oxymorphone, hydromorphone, dihydromorphine, noscapine,papaverine, papaveretum, alfentanil, buprenorphine and tramadolpharmaceutically acceptable derivatives, salts, pro-drugs and/ortautomers thereof.
 37. The method according to claim 36 wherein theopioid is morphine or a pharmaceutically acceptable salt thereof. 38.The method according to claim 36 wherein the opioid is oxycodone or apharmaceutically acceptable salt thereof.
 39. The method according toclaim 36 wherein the opioid is fentanyl or a pharmaceutically acceptablesalt thereof.
 40. The method according to claim 27 wherein at least oneof the compounds are administered orally.
 41. The method according toclaim 27 wherein at least one of the compounds are administeredintravenously, intramuscularly, intraperitoneally, intragastrically,intestinally, transdermally or intrathecally.
 42. The method accordingto claim 27 wherein the neuropathic pain is selected from the groupconsisting of monoradiculopathies, trigeminal neuralgia, postherpeticneuralgia, phantom limb pain, complex regional pain syndromes,neuropathic pain associated with AIDS or infection with the humanimmunodeficiency virus and drug-induced and diabetic neuropathy.
 43. Themethod according to claim 27 wherein the mammal is a human.
 44. Themethod according to claim 27 wherein the compound according to formula Ior pharmaceutically acceptable derivative thereof is administered at amaximum dose of 2 grams/70 kg every six hours.
 45. The method accordingto claim 27 which does not result in overt sedation.
 46. The methodaccording to claim 27 wherein the compound of formula I, orpharmaceutically acceptable derivative, and the opioid are administeredin a synergistically effective amount.
 47. A kit for inducing analgesiain response to neuropathic pain in a mammal which comprises an analgesiccompound and a compound of formula I

wherein R₁ is H, OH, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR;R₂ is H, OH, OR or ═O; R₃ is H, OH or C₁-C₄ alkyl; R₄ is H, OH, ═O,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR; R₅ is H, OH, C₁-C₄alky, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR; R₆ is H, OH, ═CH₂ or C₁-C₄alkyl; R₇ is H, OH, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl,SH, SR or —OR; and R is C₁-C₄ alkyl, C₂-C₂ alkenyl or C₂-C₄ alkanoyl; ora pharmaceutically acceptable derivative thereof.
 48. A composition forinducing analgesia, without overt sedation, in response to neuropathicpain in a mammal comprising a compound of formula I

wherein R₁ is H, OH, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR;R₂ is H, OH, OR or ═O; R₃ is H, OH or C₁-C₄ alkyl; R₄ is H, OH, ═O,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR; R₅ is H, OH, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl or —OR; R₆ is H, OH, ═CH₂ or C₁-C₄alkyl; R₇ is H, OH, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkanoyl,SH, SR or —OR; and R is C₁-C₄ alkyl, C₂-C₂ alkenyl or C₂-C₄ alkanoyl; ora pharmaceutically acceptable derivative thereof, together with at leastone pharmaceutically acceptable additive.